Substituted 3-hydrazino pyridazines as hypotensives

ABSTRACT

Certain 4-amino-6-chloro-3-hydrazino pyridazines have been found to be useful as hypotensives.

152 U.S. Cl

United States Patent [72] Inventors PaulL. Anderson Denville; William J. Houlihan, Mountain Lakes; Robert E. Manning, Mountain Lakes, all of NJ.

[21] AppLNo. 809,944

[22] Filed Mar. 24, 1969 [45] Patented Nov. 23, 1971 v [73] Assignee Sandoe-WanderJnc.

Hanover,N.J.

[54] SUBSTITUTED 3-HYDRAZINO PYRIDAZINES AS HYPOTENSIVES 3 Claims, No Drawings 5] 1m. c|;'...II A6lk 27/00 Leiter et al., Cancer Research, Vol. 25, Part 2, No. ll, December I965, pages 1779- 1788, 1791, 1793 and i829 (No. 68296) Primary Examiner-Jerome D. Goldberg Attorneys-Gerald D. Sharkin, Frederick H. Weinfeldt,

Robert S Honor, Walter F. Jewell and Richard E. Vila ABSTRACT: Certain 4-amino-6-chloro-3hydrazino pyridazines have been found to be useful as hypotensives.

SUBSTITUTED 3-HYDRAZINO PYRIDAZINES AS HYPOTENSIVES This invention relates to pyridazine derivatives. More particularly, this invention concerns the hypotensive use of 4- amino-6-chloro-3-hydrazino pyridazines and acid addition salts thereof. The invention also relates to pharmaceutical compositions containing the above compounds as an active ingredient thereof.

The active agents with which this invention is concerned may be represented by the following structural formula HIIIR where R represents a hydrogen atom or a methyl group.

The compounds of formula (I) above are known and may be prepared according to methods disclosed in the literature from known Enaterials. The present invention only contemplates the novel use of such compounds, particularly as a hypotensive agents.

As previously indicated, the compounds of formula (I) are useful because they possess pharmacological activity in animals, particularly as hypotensives as indicated by their activity in renal hypertensive rat given 30 mgJkg. of active compound using the technique of A Grollman (Proc. Soc. Exptl. Biol. and Med. S7zl02, 1944) and indirectly measuring the blood pressure from the caudal artery in the tail using a pneumatic pulse transducer. For such usage, the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions, and the like; e.g., a sterile injectable aqueous suspension. The compositions for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain up to about 90percent of the active ingredient in combination with the carrier or adjuvant. Furthermore, these compounds of formula (I) may be similarly administered in the form of their nontoxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzene-sulfonate maleate, malate tartrate, methanesulfonate, cyclohexylsufamate and the like.

The dosage of active ingredient employed for the alleviation of hypertension may vary depending on the particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds (I) are administered at a daily dosage of from about 1.0 milligram to about 50 milligrams kilogram of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about to about 350 milligrams. Dosage forms suitable for internal use comprise from about 15 to about milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets.

The following examples are provided for the purpose of illustration and not by way of limitation. They are not intended so as to limit the scope of the invention as defined in the appended claims.

EXAMPLE 1 6-chlore-3-hydrazino-4-methylamino 50 pyridazine hydrochloride tragacanth lactose corn starch talcum magnesium stearate EXAMPLE 2 Dry Filled Capsules Capsules suitable for oral administration which contain the following ingredients are prepared in a conventional manner. Such capsules are useful in treating hypertension at a dose of one capsule two to four times a day.

Ingredient Weight (mg) 4-amino-6-chloro-3-hydrazino pyridazine Inert solid diluent (starch, lactose, kaolin) EXAMPLE 3 Sterile Solution for Injection The following ingredients are dissolved in water for injection. The resulting action is filtered through an appropriate medium to render a clear solution. The solution is then autoclaved to render it sterile.

Water for injection To desired volume EXAMPLE 4 The following formulations for syrups or elixirs containing an effective amount of active compound may be formulated using conventional methods.

Percent by weight M Syrup Elixir G-chloro-3-hydrazino-4-methylamino pyridazine hydrochloride .6-3. 6 .5-3. Buffering system; Quantity sufficient to adjust pI-I l. A method for treating hypertension, which comprises orally or parenterally administering to a mammal in need of said treatment an antihypertensive effective amount of a compound of the formula HIIIR where R represents hydrogen or methyl, or a nontoxic pharmaceutically acceptable acid addition salt thereof.

2. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment at a daily dose of from about milligrams to about 350 milligrams.

3. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment in a unit dosage form comprising said compound to the extent of from about 15 milligrams to about 176 milligrams per unit dosage.

i t i ll! 

2. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment at a daily dose of from about 70 milligrams to about 350 milligrams.
 3. A method according to claim 1 wherein the compound is administered to a mammal in need of said treatment in a unit dosage form comprising said compound to the extent of from about 15 milligrams to about 176 milligrams per unit dosage. 